The immune system has evolved specifically to detect and eliminate foreign or new material from a host. This material may be of viral, bacterial, or parasitic origin and may reside outside or within the cells of the host, or be of neoplastic origin.
The non-specific or innate immune system is usually the first line of defence to a new challenge. It comprises of barriers such as skin and mucous and specialist cells such as neutrophils and macrophages which are programmed to destroy foreign material by the secretion of enzymes or by engulfing it (phagocytosis). The innate immune system can be triggered by receptors on the surfaces of phagocytes (pattern receptors or Toll like receptors) which recognise general features of the foreign substances (PAMPS). At least 10 toll receptors are known, for example, TLR4 recognises lipopolysaccharides (LPS) from bacterial cell walls and TLR9 recognises the CpG DNA sequence. Phagocytes, when activated, release inflammatory cytokines which recruit cells involved with the primary specific immune response, such as T-cells. In addition many phagocytes can also act as antigen presenting cells (APC's) by internally processing foreign proteins and presenting fragments (epitopes) of them to the recruited specific cells of the acquired immune system as a prelude to the development of a specific immune response.
The specific immune response is generally either cell mediated, wherein killer T-cells destroy infected cells, or humoral, in which antibodies such as IgG bind to the foreign material and aid the process of destruction and removal from the body by the complement system and phagocytosis. In all cases, APCs present the epitopes to T-helper cells (Th) which, depending on the signalling cytokine profile from the APC and the T-helper cell type, produces a range of Th-cell responses. Th1 like responses are cell mediated and the T-cell secretes γ interferon as the primary cytokine. Th2 like responses are humoral and are mediated in part by the secreted cytokine interleukin 4. Activated Th2 cells help to activate resting B-cells ultimately resulting in antibody production. The specific immune response normally takes 10-14 days to develop.
In almost all primary specific immune responses acute inflammation is often found at the site of the lesion. IgG1 and IgE are known as inflammatory antibodies because they either activate the complement system or initiate the release of inflammatory cytokines from mast cells or basophils.
The complement system is a set of plasma proteins that act together to attack extracellular forms of pathogens. Complement results in the opsonization of pathogens, the recruitment of inflammatory cells and directs the killing of pathogens. The complement system can be activated by two different pathways: the classical complement pathway and the alternative complement pathway. The classical pathway is antibody-dependent and is activated by the binding of antibody molecules (specifically IgM and IgG1, IgG2, and IgG3) to a foreign particle. The role of complement in inflammation and tissue injury has become apparent through clinical investigations and discoveries that the pathogenesis of certain experimental inflammatory diseases is complement-dependent.
Mast cells, located in perivascular connective tissue throughout the body, are involved in Type I allergic disease. Type I Allergic disease is a disease of the developed world which affects up to 30% of the population of the USA and Europe. IgE mediated allergy is also implicated in asthma and over 70% of asthmatics are allergic to one or more allergen. The cost of allergic disease probably exceeds $10 billion in the USA alone. When inhaled or trapped on mucosal surfaces, pollens release proteins (allergens) which, in some individuals, results in an acute inflammatory response mediated by allergen specific IgE antibodies bound to mast cells. The allergic reaction is triggered when the allergens cross-link preformed IgE, bound to mast cells, resulting in de-granulation of the mast cell and the release of copious amount of inflammatory mediators including histamine. In severe cases allergic disease can result in asthma and anaphylaxis, a life threatening condition.
In contrast to the initiation of the immune response, much less is known about the resolution of inflammation following an antigen or allergen challenge. It is thought that another class of T-cell is involved, the so called regulatory T-cell or T-reg. These cells under the influence of anti-inflammatory cytokines TNFβ and interleukin 10, which are involved in dampening down the T-cell responses, switch the antibody responses to IgA and IgG4 both of which are non-inflammatory antibodies and do not activate the complement system. Secretory IgA (sIgA) is found on mucous membranes and has been shown to neutralize viruses and prevent their adherence to the epithelial cells lining the mucous. McCluskie et al., MICROBES INFECT. 1(9):685-98 (1999); Ogra et al., CLIN MICROBIOL REV. 14(2):430-45 (2001); Rosenthal et al., SEMIN IMMUNOL. 9(5):303-14 (1997); van Ginkel et al., EMERG INFECT DIS. 6(2):123-32 (2000).
Recent studies on the mechanism of removal of inflammatory cells such as neutrophils from the site of an inflammatory lesion have focused on the rapid turnover and apoptosis of these cells. Neutrophils are phagocytes and, after they have engulfed foreign material, a safe and effective way of their disposal is needed. Macrophages, having engulfed a dying neutrophil, undergo significant changes which alter their pattern of cytokine secretion (Fadok et al, J. CLIN. INVEST. 101:890-898 (1998)), switching production from inflammatory cytokine to anti-inflammatory cytokine synthesis which include, among others, TGFβ.
It has recently been shown that phosphatidylserine may be a general recognition marker for the removal of apoptotic cells, such as neutrophils, by phagocytes (Fadok et al., NATURE 405:85-90 (2000)), while U.S. Pat. No. 6,953,591 to Belyaysky et al. discloses the use of phosphatidylserine for treating T-cell-mediated diseases.